Abstract Immunotherapy has become a game changer for about 20% of patients with metastatic cancers who until now would die quickly of their disease. This new class of immunotherapies induce durable responses that can last for years without further therapy. These agents (immune checkpoint inhibitors) act on T cells that are inactivated due to immune checkpoint signals that inhibit their infiltration into and function within tumors. But for about 80% of patients, immunotherapy has not been effective, and immune unresponsiveness is likely the result of failure to activate effector T cells together with the existence of multiple suppressive signals rather than a predominant immune checkpoint signal within resistant tumors. Accumulating data suggests that it is possible to convert non-immunogenic tumors into one that respond to immunotherapy. Thus, this proposal will address the next big question in cancer immunotherapy: why do some cancers respond to checkpoint immunotherapy and exhibit durable responses, while others either develop resistance (adaptive resistance) or are naturally resistant. Understanding primary and adaptive resistance mechanisms will translate into effective scientifically driven combination immunotherapies that combat resistance. Our group has led the development of both single agent and combination therapy for pancreatic adenocarcionoma (PDA) and colorectal carcinoma (CRC) and have recently received FDA approval for Pembrolizumab for the treatment of patients with microsatellite instability (MSI) high tumors. In addition, we have shown that treatment of patients with a vaccine can induce cancer specific T cells that infiltrate into PDA and CRC tumors, opening the door for novel combination immunotherapies. In this proposal, we will use specimens already collected and prospectively being collected on trials that are demonstrating both sensitivity and primary and adaptive resistance to immunotherapies, to define additional signals required to convert insensitive tumors into ones that respond to immunotherapy.